Ofatumumab in CLL

Multicenter Clinical Trial of ARZERRA® (ofatumumab), a Novel Anti-CD20 Monoclonal Antibody, in Patients with Chronic Lymphocytic Leukemia (CLL) Refractory to Fludarabine and Alemtuzumab ABSTRACT BACKGROUND Patients with progressive, refractory CLL who have received multiple lines of therapy, including fludarabine, alemtuzumab, alkylating agents, and rituximab, are in need of additional active and well tolerated treatment options. Many of these patients are older and present with a number of poor prognostic factors. ARZERRA is an anti-CD20 monoclonal antibody FDA-approved for the treatment of patients with CLL refractory to fludarabine and alemtuzumab.

PATIENTS AND METHODS The ARZERRA pivotal study was a single-arm, multicenter study in 154 patients with relapsed or refractory CLL. Fifty-nine patients with CLL refractory to fludarabine and alemtuzumab comprised the efficacy population; median age was 64 years (range, 41-86 years), 75% were male, and 95% were Caucasian. The median number of prior therapies in the efficacy population was 5; 93% received prior alkylating agents, 59% received prior rituximab, and all received prior fludarabine and alemtuzumab.

Patients received 8 weekly infusions of ARZERRA followed by 4 monthly infusions during a 24-week period (dose 1, 300 mg; doses 2 to 12, 2000 mg). The main efficacy outcome was durable objective tumor response rate, determined using the 1996 National Cancer Institute Working Group (NCIWG) Guidelines for CLL. RESULTS The investigator-determined overall response rate with single-agent ARZERRA was 42% (99% CI: 26, 60), with a median duration of response of 6.5 months (95% CI: 5.8, 8.3). There were no complete responses. Median time to onset of response was 1.8 months (95% CI: 3.7, 7.6); with more than 40% of patients responding after 4 weeks, and approximately 70% of patients responding after 8 weeks. In the efficacy population, 88% of patients received at least 8 infusions of ARZERRA and 54% received all 12 infusions. Response rates observed with ARZERRA monotherapy were independent of prior exposure to rituximab, including refractoriness to FCR (fludarabine cyclosphosphamide rituximab).. Advanced age did not diminish the efficacy of ARZERRA, with responses seen in patients ≥65 years of age similar to those in patients <65 years. No data demonstrated an improvement in disease-related symptoms or increased survival. The most common serious adverse events observed with ARZERRA in the total patient population (n=154) were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Overall infusion-related adverse events were most common on the day of the first infusion (44%), declined at the second dose (29%), and decreased further with subsequent infusions. The majority of infusion reactions were Grades 1 to 2 in severity; grades 3-4 infusion reactions occurred in only 0 to 2% per infusion. A total of 108 (70%) patients experienced bacterial, viral, or fungal infections; 45 (29%) patients experienced Grade 3 or higher infections; 19 (12%) were fatal. In the fludarabine and alemtuzumab-refractory group, 17% of infections were fatal. A majority of infections seen with ARZERRA were Grade 1 or 2 in severity CONCLUSIONS As a single agent, ARZERRA achieved a 42% response rate in a population of patients with CLL refractory to fludarabine and alemtuzumab who had received a median of 5 prior CLL therapies. Responses were observed as early as 4 weeks and were sustained at all assessment times during the treatment period. The most common serious adverse events were infections, neutropenia, and pyrexia. No unexpected adverse events were reported. Infusion reactions occurring with ARZERRA were mostly mild to moderate and decreased over the course of continued treatment. In conclusion, monotherapy with ARZERRA is an active and generally well-tolerated regimen in heavily pre-treated patients with CLL refractory to fludarabine and alemtuzumab.

Patients with progressive CLL who are refractory to fludarabine (including fludarabine-based regimens) and alemtuzumab are considered to have a poor prognosis.7,8 Many of these patients have also progressed through several single-agent and combination CLL therapies, including rituximab and alkylating agents. These older, poor prognosis populations have an unmet medical need for an active CLL treatment option with a manageable safety and tolerability profile.

INTRODUCTION Chronic lymphocytic leukemia (CLL) is the most commonly diagnosed adult leukemia1, accounting for about 1 in 3 of all leukemias.2 CLL mainly affects older adults, occurring slightly more often in males2. The disease is most prevalent in individuals in their 7th, 8th, and 9th decades of life.3 At the time of diagnosis, the median age is around 72 years,4 and approximately 9 of 10 patients already have 1 or more comorbidities.5 Initial therapeutic options for CLL may include single-agent and combination regimens consisting of steroids, chemotherapy and monoclonal antibodies. Treatment can span over a number of years. During the later phase of CLL, morbidity is considerable, both from the disease itself and from the complications of therapy.6 All patients eventually experience disease progression, and effective therapeutic options become limited.

ARZERRA® (ofatumumab) is a targeted, CD20-directed cytolytic monoclonal antibody indicated for the treatment of patients with CLL refractory to fludarabine and alemtuzumab.9 ARZERRA was granted accelerated approval by the FDA on October 26, 2009. The effectiveness of ARZERRA is based on the demonstration of durable objective responses. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. −1−

Figure 2. Proposed CDC activity with ARZERRA 9,12-15,17-18

This review presents a summary of the efficacy and safety results from the ARZERRA pivotal trial, a single-arm, multicenter international study of single-agent ARZERRA in the treatment of 154 patients with relapsed or refractory CLL.9-11 Fifty-nine patients with CLL refractory to fludarabine and alemtuzumab comprised the efficacy population.

Overview of ARZERRA ARZERRA is a targeted, human anti-CD20 monoclonal antibody that targets both the small and large extracellular loops on the CD20 molecule (Figure 1). The CD20 molecule is expressed on normal B lymphocytes (pre-B- to mature B-lymphocyte) and on B-cell CLL.9 Figure 1. ARZERRA mechanism of action 9

ARZERRA binds to CD20, ▼

Attracts the first complement component (C1), and ▼

Activates the complement cascade, ▼

Which creates the membrane attack complex (MAC) that ▼

Forms a pore in the cell membrane, ▼

Causing osmotic lysis of the B cell

PATIENTS AND METHODS

Based on in vitro data, ARZERRA is thought to induce B-cell CLL destruction by two mechanisms:9,12,13

Study Design 9,10 The ARZERRA pivotal study was a single-arm, multi-center, international trial of 154 patients with relapsed or refractory CLL; 59 patients with CLL refractory to fludarabine and alemtuzumab comprised the efficacy population (sometimes referred to as FA-refractory CLL). Drug refractoriness was defined as failure to achieve at least a partial response to, or disease progression within 6 months of, the last dose of fludarabine or alemtuzumab.

No randomization was performed in this trial.

• Complement-dependent cytotoxicity (CDC). CD20-bound ARZERRA activates the complement cascade, which induces B-cell osmotic lysis (Figure 2) • Antibody-dependent cellular cytotoxicity (ADCC). Phagocytic cells bind to CD20-bound ARZERRA, which release mediators that damage, destroy, and engulf B cells Study investigators suggested that the potent CDC with ARZERRA may be a result of the close proximity of the smallloop binding site to the cell surface, potentially leading to more effective deposition of complement on the cell surface.11,13-16

The main efficacy outcome was durable objective tumor response rate. Tumor responses were determined using the 1996 NCI Working Group Guidelines for CLL. Responses were required to be maintained for at least 2 months. Other efficacy endpoints discussed in this review include: time to onset of response, duration of response, response by patients’ years of age, and response by number of prior CLL treatments

ARZERRA is a different anti-CD20 because it strongly binds to the small loop epitope close to the cell membrane on the CD20 protein. The distinctive target of ARZERRA is due to its fully human origin. All known human anti-CD20 antibodies target the combined small and large loop epitope, while all known mouse-derived anti-CD20 antibodies target only the large loop.

Objective responses presented in this review were assessed by study investigators. Other outcome measures were assessed

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by independent review committee (IRC). The algorithmic approach used for the investigator assessment of objective response represented a more stringent test of the objective response rate compared with the IRC assessment. Severity of adverse events (AEs) was graded by investigators according to the NCI Common Terminology Criteria for Adverse Events (version 3.0).

the glucocorticoid dose could be reduced to less than 100 mg for other infusions. Anti-infective prophylaxis was not mandated.

This multi-center international trial was conducted at 41 sites in 10 countries, including the United States (9 sites).

United Kingdom (5 sites), Czech Republic (4 sites), Denmark (2 sites), Germany (7 sites), Italy (2 sites), Poland (5 sites), Spain (1 site), France (4 sites), and Sweden (2 sites).

The pivotal study was comprised of 3 periods (Figure 3): 10

The ARZERRA pivotal trial was purposely designed as a non-randomized study. At the time of enrollment, no single standard of care had had emerged for patients with CLL refractory to fludarabine and alemtuzumab. Study investigators noted it would be difficult to enroll patients in a randomized trial with an experimental arm of potentially high efficacy and tolerable safety, for comparison to regimens with low response rates and substantial toxicity or best supportive care.

− Treatment (up to 24 weeks): ARZERRA 300 mg (infusion 1, week 0); 2,000 mg weekly for 7 infusions (weeks 1 - 7); 2,000 mg every 4 weeks for 4 infusions (weeks 12 - 24) − Follow-up (week 28 to month 24): patients were evaluated every 3 months until month 24. All patients in follow-up completed all 12 infusions. − Extended Follow-up: After completion of month 24, patients were monitored every 3 months for survival and malignant B-cell values. Monitoring continued until B-cell values reached baseline or above, or until alternative CLL therapy was initiated, or month 48.

CLL experts reviewed the safety and efficacy of ARZERRA in the context of the limited efficacy and toxicities of other salvage therapies, and agreed that a non-randomized trial would be acceptable. A non-randomized design also ensured that all patients would receive a potentially active treatment with the favorable safety profile of a monoclonal antibody when given as monotherapy.

Patients received acetaminophen 1,000 mg and cetirizine 10 mg (or equivalent) before infusions. Patients also received glucocorticoid (prednisolone 100 mg or equivalent) before infusions 1, 2, and 9; if initial infusions were well tolerated,

Figure 3. Overview of ARZERRA pivotal study design10

 300 mg ARZERRA

▼2000 mg ARZERRA

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 Response evaluation

 Follow-up contact

Patient Characteristics 9,10 .

Patients enrolled in the ARZERRA pivotal trial were representative of a population with advanced, refractory CLL encountered in clinical practice. The total trial population included 154 adult patients (≥18 years of age) with relapsed or refractory CLL; the 59 patients in the efficacy subgroup were refractory to fludarabine and alemtuzumab.

Eligibility for enrollment included: active CLL disease with an indication for treatment, tumor immunophenotype of CD5+/20+/23+, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and life expectancy of at least 6 months. Refractoriness to fludarabine (at least two cycles) and alemtuzumab (at least 12 doses) was defined as failure to achieve at least partial response (PR) by 1996 NCI-WG criteria or disease progression during treatment or within 6 months of the last dose of each agent Baseline characteristics for the 59 patients in the ARZERRA efficacy population are summarized below, including demographics and disease characteristics (Table 1); hematology parameters (Table 2), and number of prior CLL therapies (Table 3).

The majority of patients were older males with advanced stage, active CLL. Almost half of the patients were over 65 years old, which is considered an adverse prognostic indicator in CLL treatment; median age was 64 years (range, 41-86 years). Seventy-five percent of patients were male; 95% were Caucasian; 54% were Rai Stage III or IV disease; and 78% had an had an impairment of their daily living abilities with an ECOG performance status of 1 or 2.

Hematology parameters, including baseline cytopenias, were also consistent with advanced stage CLL refractory to fludarabine and alemtuzumab. Median lymphocyte count was above normal; median platelet counts and hemoglobin levels were below normal; and median neutrophil counts were within the normal range.

Patients enrolled in the ARZERRA pivotal study had already received most of the available CLL treatments and regimens both as single agents and in combinations. More than 2 prior CLL therapies is an adverse prognostic indicator in CLL treatment19 and patients in the FA-refractory efficacy population had a median of 5 prior CLL treatment regimens.

Ninety-three percent had received prior alkylating agents; 59% received prior rituximab; 37% of patients were refractory to FCR (fludarabine, rituximab, cyclophosphamide), and all patients received prior fludarabine and alemtuzumab.

Concurrent medical conditions at screening included hypertension, anemia, thrombocytopenia, drug hypersensitivity, enlarged prostate, cough and fatigue, which are typical for CLL patients in this age group. −4−

Table 1. Selected Baseline Demographic and Disease Characteristics in the Efficacy Population, (n=59) 10 Male

75%

Median age, years Range ≥ 65 years

64 years 41 to 86 46%

Caucasian, %

95%

Median duration of CLL in years Min, max

6 years 1, 18.6

Rai Stage I / II III / IV

44% 54%

ECOG Performance Status Stage 0 Stage 1 Stage 2

46% 32% 20%

Bulky lymphadenopathy (≥1 lymph node >5cm by CT scan)

93%

Table 2. Summary of Baseline Hematology Parameters, Cytopenias and Anemia for Efficacy Population, (n=59) 10 Lymphocytes (x 109/L) Median (range)

n=56 14.7 (0, 260)

Neutrophils (x 109/L) Median (range)

n=57 2.1 (0,129)

Platelets (x 109/L) Median (range)

n=59 101 (9,373)

Hemoglobin (g/dL) Median (range)

n=56 11.4 (7,18)

Neutropenia

10%

Thrombocytopenia

12%

Anemia

22%

Table 3. Prior CLL Therapies at Baseline in the Efficacy Population (n=59) 10 Median Number of Prior CLL Therapies Range 1 -2 Prior Therapies 3-5 Prior Therapies >5 Prior Therapies Prior CLL Therapy Fludarabine Alemtuzumab Alkylating agents Any Rituximab FCR Single-agent cytotoxics Combination chemotherapy Other*

5 1 to14 11% 42% 46% 100% 100% 93% 59% 37% 68% 37% 37%

* Other therapy includes investigational drugs and investigational or off-label use of approved drugs (i.e.,lenalidomide, thalidomide).

RESULTS

Figure 4. Overall Responses Rate (%) With ARZERRA 9 Monotherapy in the Efficacy Population (n=59)

Efficacy 9,10 In a population of patients with FA-refractory CLL who had received a median of 5 prior CLL therapies (n=59), the investigator-determined overall response rate with singleagent ARZERRA was 42% (99% CI: 26, 60) [Figure 1]. There were no complete responses reported. Stable disease was observed in 18 patients (31%); progressive disease occurred in 2 patients (3%). No data demonstrated an improvement in disease-related symptoms or increased survival.

In the efficacy population, 88% of patients received at least 8 infusions of ARZERRA and 54% received all 12 infusions (Figure 2). This correlated with a rapid onset of response, with over 40% of patients responding by the 1st assessment (4 wks) and around 70% by the 2nd assessment (8 wks). Median time to onset of response was 1.8 months (95% CI: 3.7, 7.6) [Figure 3]. Corresponding with the rapid onset of response was a rapid decrease of leukemic cells in blood, with significant reductions in CLL cells seen within 1 week, and near complete elimination within 4 weeks.

Responses with ARZERRA were maintained after the last infusion for more than 2 months in over 50% of responders and up to 9 months in approximately 10% of responders.

The median duration of response was 6.5 months (95% CI: 5.8, 8.3) [Figure 4]. The relatively rapid return of disease after completion of treatment is typical in a refractory CLL patient population

Table 4. Objective response rates with ARZERRA monotherapy, with or without prior rituximab use, in the Efficacy Population 10

The number of prior CLL treatment regimens did not appear to influence the response to ARZERRA. Patients with 3 or more prior CLL treatments, which accounted for almost 90% of the efficacy population, had a response rate of 52%. In addition, responses seen with ARZERRA monotherapy were independent of prior exposure to rituximab, which comprised 57% of patients in the efficacy population. Overall, the response rates for patients previously treated with rituximab, including those who were FCR-refractory, were not different from patients with no prior rituximab (Table 3).

Population

Number of Patients, Response Rate

Prior Rituximab, N Response rate (%)

35 patients 54%

FCR refractory Response rate (%)

16 patients 50%

No prior Rituximab, N Response rate (%)

24 patients 63%

Overall population, N Response rate (%)

59 patients 42%

Table 5. Objective response rates with ARZERRA monotherapy by patient age 10

Response rates in patients 65 years and older were similar to those seen in patients under 65 years (Table 4).

In CLL, responses to treatment are usually diminished in elderly patients, which accounted for 46% of the efficacy population. Still, at least 50% of patients 65, 70, and even 75 years or older responded to single-agent ARZERRA. Response rates greater than 50% were also seen with ARZERRA monotherapy regardless of certain baseline disease characteristics, including lymph node size, Rai disease stage, and performance status. −5−

Population

Number of Patients, Response Rate

Age < 65 years, N Response rate (%)

32 patients 65%

Age ≥ 65 years, N Response rate (%)

27 patients 52%

Age ≥ 70 years, N Response rate (%)

10 patients 60%

Figure 5. Percent of patients receiving ARZERRA infusions over time in the efficacy population (n=59) 10

Figure 6. Median time to onset of response to ARZERRA monotherapy, Responders only 10

Figure 7. Median duration of response with ARZERRA monotherapy, Responders only 10

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Safety 9,10 ARZERRA treatment. As the number of infusions increased, the need to manage these AEs lessened. Overall, the infusion reaction profile is consistent with expectations of anti-CD20 monoclonal antibody therapy in CLL.

The safety of monotherapy with ARZERRA was evaluated in a 181 patients with relapsed or refractory CLL in 2 openlabel, non-randomized, single-arm studies, which included the pivotal study (Study 1, n=154) and a dose-escalating study (Study 2, n=27). Adverse event (AE) data described in this review were derived from the 154 patients in the pivotal study and from the subset of 59 patients from the efficacy population with FA-refractory CLL All patients received 2,000 mg weekly from . the second dose onward.

AEs by baseline characteristics: The incidence of AEs was similar among patients <65 years of age,≥65 years of age, and ≥75 years of age. The percent of patients with AEs was also similar among the Rai stage subgroups, with no clinically meaningful differences observed among the different Rai stages with regard to type of AEs reported during treatment or follow-up.

The overall incidence of AEs was slightly lower in patients with only 1-2 previous CLL treatments than in patients with 3 or more previous treatments.

In this study of poor prognosis patients who had progressed through several lines on CLL therapy, the most common serious AEs observed during monotherapy with ARZERRA included: infections (pneumonia and sepsis), neutropenia, and pyrexia (Table 5). Infusion reactions were also common, but were mostly mild-to-moderate in severity and decreased with continued therapy (Figure 5). The incidence of AEs was generally similar between the 154 patients from the pivotal study and the subgroup of 59 FA-refractory patients.

The majority of AEs (81%) occurred during treatment, and no unexpected AEs were reported. No host antibodies against ARZERRA (human anti-human antibodies, HAHA) were detected.

Withdrawals from therapy: Of the 69 patients who withdrew from treatment, half were due to progressive disease. Only a minority of total patients (14%) withdrew from treatment due to AEs; 20% of patients in the FA-refractory group withdrew due to AEs. Grade 3 AEs were observed in over 50% of patients, although half were classified as non-serious. Overall, the safety profile with ARZERRA monotherapy was in accordance with what could be expected from an anti-CD monoclonal antibody.

An overview of AEs and withdrawals is presented in Table 6.

Infections: A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 (12%) were fatal.

Infection rates decreased with increasing time on treatment.

The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. A majority of infections seen with ARZERRA were Grade 1 or 2 in severity.

Table 6. Overview of Serious and Grade 3 AEs during treatment with ARZERRA or during follow-up 10

Neutropenia: Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 neutropenia.

Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia greater than 2 weeks in duration.

Infusion reactions: Infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2000 mg), and less frequently during subsequent infusions. The majority of infusion reactions were Grades 1 to 2 in severity and decreased over the course of continued treatment; grades 3-4 infusion reactions occurred in only 0 to 2% per infusion. No fatal infusion reactions were reported. Ninety percent of the 154 patients in the pivotal study received at least 8 infusions; 85 patients completed all 12 infusions.

Total Treated (n=154), %

FA-refractory (n=59), %

Fatal serious AEs

16%

20%

Non-fatal serious AEs

47%

46%

AEs Grade 3 or higher

57%

64%

Grade 3 non-serious AEs

24%

25%

Any Infections

70%

69%

AEs leading to withdrawal

14%

20%

Please see additional Important Safety Information on pages X–X and accompanying complete Prescribing Information.

The use of standard pre-medications, which included paracetamol, antihistamine and IV steroids, helped manage the occurrence and severity of infusion-related AEs at the start of −7−

Table 7. AEs occurring in >5% of patients treated with ARZERRA Monotherapy 9

*Pneumonia includes pneumonia, lung infection, lobar pneumonia, and bronchopneumonia. †Rash includes rash, rash macular, and rash vesicular. ‡Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock

Figure 8. Percentage of patients with relapsed or refractory CLL who experienced infusion reactions by infusions (total study population, n=154) 10

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viral, or fungal infections; 45 (29%) patients experienced ≥Grade 3 infections; 19 (12%) were fatal. In the fludarabine and alemtuzumab-refractory group, 17% of infections were fatal. The incidence of grade 3 or 4 infections was at an expected level, considering the number of prior CLL treatments and the extent of disease among these patients. A majority of infections seen with ARZERRA were Grade 1 or 2 in severity.10

DISCUSSION CLL remains a very challenging disease to treat in the later phases, as most patients are older and have progressed through 2 or more CLL therapies. In this study, single-agent ARZERRA demonstrated significant activity in a population of patients with advanced stage CLL refractory to fludarabine and alemtuzumab. Patients who received a median of 5 prior CLL therapies achieved an impressive 42% overall response rate with ARZERRA monotherapy (99% CI: 26, 60).9 There were no complete responses and no data demonstrated an improvement in disease-related symptoms or increased survival. These results are especially encouraging for a single agent used in such heavily pretreated patients in this setting.

Infusion-related AEs were most common on the day of the first infusion (44%), declined at the second dose (29%), and subsided further with subsequent infusions. The majority of infusion reactions were Grades 1 to 2 in severity; grades 3-4 infusion reactions occurred in only 0 to 2% per infusion.

Overall, the ARZERRA infusion schedule was generally well tolerated, supported by the finding that 90% of the 154 patients in the pivotal study received at least 8 infusions, representing the most intense period of the treatment schedule. As the number of infusions increased, the need to manage infusion AEs lessened.10

The majority of patients (88%) received at least 8 infusions of ARZERRA and 54% completed all 12 infusions.

This correlated with a rapid onset of response, with more than 40% of patients responding by the first assessment at 4 weeks, and approximately 70% by the next assessment at 8 weeks.

The median time to overall response was 1.8 months (95% CI: 3.7, 7.6). The responses were sustained during the treatment period. The median duration of response was 6.5 months (95% CI: 5.8, 8.3).9,10 Investigators noted that with a median response duration of 6 to 7 months, some patients experienced relapse soon after completing treatment. One possible explanation for this is the proliferative nature of disease in these refractory CLL patients.10,11

Among patients who withdrew from treatment, half were due to progressive disease. Only a minority of total patients (14%) withdrew from treatment due to AEs; in the efficacy population, 20% of patients withdrew due to AEs.10

CONCLUSIONS In conclusion, monotherapy with ARZERRA is an active and generally well managed regimen in heavily pre-treated patients with CLL refractory to fludarabine and alemtuzumab. As a single agent, ARZERRA achieved a 42% response rate in a population of patients with CLL refractory to fludarabine and alemtuzumab who had received a median of 5 prior CLL therapies. Responses were observed as early as 4 weeks and were sustained at all assessment times during the 24-week treatment period. The most common serious AEs were infections, neutropenia, and pyrexia. No unexpected AEs were reported. No formation of human anti-human antibodies was detected. 9,10

Patients responded independent of the number of prior therapies, including prior rituximab use, and older age.10 Patients with 3 or more prior CLL treatments, which comprised almost 9 out of 10 patients in had a response rate of 52%.

Patients with prior exposure to rituximab, which accounted for the majority of the efficacy population, had a 54% response rate. Response rates in patients 65 years and older (>50%) were similar to those seen in patients under 65 years (65%).

Investigators also noted that the dose of corticosteroid premedication used in this study has not been reported to have efficacy in refractory patients with CLL and was not likely to significantly affect the objective response rate.11

Given the unmet medical need in this study population, ARZERRA can provide hope for patients with CLL refractory to fludarabine and alemtuzumab who currently have few, if any, additional treatment options.

Monotherapy with ARZERRA was generally well tolerated.9,10 The most common serious AEs observed with ARZERRA in the total patient population (n=154) were infections (including pneumonia and sepsis), neutropenia, and pyrexia. A total of 108 (70%) patients experienced bacterial,

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15. Beum PV, Lindorfer MA, Beurskens F, et al: Complement activation on B lymphocytes opsonized with rituximab or ofatumumab produces substantial changes in membrane structure preceding cell lysis. J Immunol 181:822-832, 2008 16. Pawluczkowycz A, Beurskens F, Beum P, et al: Binding of submaximal C1q promotes complement dependent cytotoxicity (CDC) of B cells opsonized with anti-CD20 mAbs ofatumumab (OFA) or rituximab (RTX): Considerably higher levels of CDC are induced by OFA than by RTX. J Immunol 183: 749-758, 2009 17. Shernan SK, Collard CD. Role of the Complement System in Ischaemic Heart Disease: Potential for Pharmacological Intervention BioDrugs. 2001;15(9):595-607.

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